In this application for a Mentored Research Scientist Development Award (K01), Dr. Kyle Simmons requests support to acquire the training necessary to establish himself as an independent neuroscientist studying aberrant feeding behaviors in depression. Depression-related changes in feeding, which can be manifested either as increases or decreases in appetite and weight, are important because they may both engender risk for serious physical illnesses such as obesity and its concomitant physical illnesses, and may also elucidate the differential pathophysiologies of Major Depressive Disorder (MDD). Accomplishing this long-term goal requires that Dr. Simmons develop skills that cut across disciplines, including the clinical neuroscience of depression, the neuroscience of food motivation, and functional neuroimaging. Based on his prior research track record, Dr. Simmons has demonstrated expertise in functional neuroimaging. In order to fully attain his goals, however, he needs the training and experience that comes from working with experts in the neurobiology of depression, and food motivation. To that end, Dr. Simmons will receive mentoring in the neurobiology of depression from Dr. Wayne Drevets, the former Chief of the Section on Neuroimaging in Mood and Anxiety Disorders in the NIMH Intramural Research Program, and now Director of the Laureate Institute for Brain Research (LIBR). To receive training in the neurobiology of food motivation, Dr. Simmons will work closely with Dr. Cary Savage, a respected investigator in the functional neuroimaging of food motivation. The proposed training plan also provides opportunities to acquire instruction in advanced statistical modeling, and in the neurobiology of feeding, including metabolic signaling of hunger and satiety. The training, and associated research, will take place at LIBR, a state-of-the-art institue dedicated to conducting neuroimaging and genetics research aimed developing more effective treatments for neuropsychiatric disorders. LIBR is closely affiliated with the Laureate Psychiatric Clinic and Hospital, which provides exceptional access to clinical populations available for research, particularly patients with mood disorders. With the training offered by his mentors, and institutional resources at LIBR, Dr. Simmons will be able to achieve the research objectives of this proposal, namely to determine specifically which brain regions underlie the changes in feeding behavior that characterize MDD, and the marked differences in feeding behaviors that differentiate among many MDD patients. Specifically, the proposed research will identify whether MDD is associated with aberrant activity within the OFC, vmPFC, or striatal-pallidal neurocircuit during food perception and food-related decision making (Specific Aim 1), whether hyperphagic and hypophagic MDD subtypes are associated with distinct OFC, vmPFC, or striatal-pallidal neurocircuit responses during food perception and food-related decision making (Specific Aim 2), and whether previously validated behavioral ratings of anhedonia are related to MDD patients' OFC, vmPFC, or striatal-pallidal neurocircuit responses during food perception and food-related decision making (Specific Aim 3). PUBLIC HEALTH RELEVANCE: Major depressive disorder (MDD) is the leading cause of years lived with disability worldwide, and yet relatively little is known about its underlying biological causes. One symptom upon which MDD patients exhibit marked differences is feeding behavior, with some patients eating less when they become depressed, while others eat more. It is important to understand these aberrant feeding behaviors in depression as they may both engender risk for serious physical illnesses such as obesity, metabolic syndrome, and type-2 diabetes, and may also clarify the different biological bases of MDD.